Cisplatin Neurotoxicity Targets Specific Subpopulations and K+ Channels in Tyrosine-Hydroxylase Positive Dorsal Root Ganglia Neurons
Among the features of cisplatin chemotherapy-induced peripheral neuropathy are chronic pain and innocuous mechanical hypersensitivity. The complete etiology of the latter remains unknown. Here, we show that cisplatin targets a heterogeneous population of tyrosine hydroxylase-positive (TH+) primary a...
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2022.853035/full |
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| author | Carrie J. Finno Yingying Chen Seojin Park Jeong Han Lee Maria Cristina Perez-Flores Jinsil Choi Ebenezer N. Yamoah |
| author_facet | Carrie J. Finno Yingying Chen Seojin Park Jeong Han Lee Maria Cristina Perez-Flores Jinsil Choi Ebenezer N. Yamoah |
| author_sort | Carrie J. Finno |
| collection | DOAJ |
| description | Among the features of cisplatin chemotherapy-induced peripheral neuropathy are chronic pain and innocuous mechanical hypersensitivity. The complete etiology of the latter remains unknown. Here, we show that cisplatin targets a heterogeneous population of tyrosine hydroxylase-positive (TH+) primary afferent dorsal root ganglion neurons (DRGNs) in mice, determined using single-cell transcriptome and electrophysiological analyses. TH+ DRGNs regulate innocuous mechanical sensation through C-low threshold mechanoreceptors. A differential assessment of wild-type and vitamin E deficient TH+ DRGNs revealed heterogeneity and specific functional phenotypes. The TH+ DRGNs comprise; fast-adapting eliciting one action potential (AP; 1-AP), moderately-adapting (≥2-APs), in responses to square-pulse current injection, and spontaneously active (SA). Cisplatin increased the input resistance and AP frequency but reduced the temporal coding feature of 1-AP and ≥2-APs neurons. By contrast, cisplatin has no measurable effect on the SA neurons. Vitamin E reduced the cisplatin-mediated increased excitability but did not improve the TH+ neuron temporal coding properties. Cisplatin mediates its effect by targeting outward K+ current, likely carried through K2P18.1 (Kcnk18), discovered through the differential transcriptome studies and heterologous expression. Studies show a potential new cellular target for chemotherapy-induced peripheral neuropathy and implicate the possible neuroprotective effects of vitamin E in cisplatin chemotherapy. |
| first_indexed | 2024-12-10T12:17:45Z |
| format | Article |
| id | doaj.art-c13336dd3b6b42188ad2ea415045bcef |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-10T12:17:45Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-c13336dd3b6b42188ad2ea415045bcef2022-12-22T01:49:11ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022022-05-011610.3389/fncel.2022.853035853035Cisplatin Neurotoxicity Targets Specific Subpopulations and K+ Channels in Tyrosine-Hydroxylase Positive Dorsal Root Ganglia NeuronsCarrie J. Finno0Yingying Chen1Seojin Park2Jeong Han Lee3Maria Cristina Perez-Flores4Jinsil Choi5Ebenezer N. Yamoah6Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, CA, United StatesDepartment of Physiology and Cell Biology, School of Medicine, University of Reno, Reno, NV, United StatesDepartment of Physiology and Cell Biology, School of Medicine, University of Reno, Reno, NV, United StatesDepartment of Physiology and Cell Biology, School of Medicine, University of Reno, Reno, NV, United StatesDepartment of Physiology and Cell Biology, School of Medicine, University of Reno, Reno, NV, United StatesDepartment of Physiology and Cell Biology, School of Medicine, University of Reno, Reno, NV, United StatesDepartment of Physiology and Cell Biology, School of Medicine, University of Reno, Reno, NV, United StatesAmong the features of cisplatin chemotherapy-induced peripheral neuropathy are chronic pain and innocuous mechanical hypersensitivity. The complete etiology of the latter remains unknown. Here, we show that cisplatin targets a heterogeneous population of tyrosine hydroxylase-positive (TH+) primary afferent dorsal root ganglion neurons (DRGNs) in mice, determined using single-cell transcriptome and electrophysiological analyses. TH+ DRGNs regulate innocuous mechanical sensation through C-low threshold mechanoreceptors. A differential assessment of wild-type and vitamin E deficient TH+ DRGNs revealed heterogeneity and specific functional phenotypes. The TH+ DRGNs comprise; fast-adapting eliciting one action potential (AP; 1-AP), moderately-adapting (≥2-APs), in responses to square-pulse current injection, and spontaneously active (SA). Cisplatin increased the input resistance and AP frequency but reduced the temporal coding feature of 1-AP and ≥2-APs neurons. By contrast, cisplatin has no measurable effect on the SA neurons. Vitamin E reduced the cisplatin-mediated increased excitability but did not improve the TH+ neuron temporal coding properties. Cisplatin mediates its effect by targeting outward K+ current, likely carried through K2P18.1 (Kcnk18), discovered through the differential transcriptome studies and heterologous expression. Studies show a potential new cellular target for chemotherapy-induced peripheral neuropathy and implicate the possible neuroprotective effects of vitamin E in cisplatin chemotherapy.https://www.frontiersin.org/articles/10.3389/fncel.2022.853035/fullcancerchemotherapyneuropathysensoryvitamin E |
| spellingShingle | Carrie J. Finno Yingying Chen Seojin Park Jeong Han Lee Maria Cristina Perez-Flores Jinsil Choi Ebenezer N. Yamoah Cisplatin Neurotoxicity Targets Specific Subpopulations and K+ Channels in Tyrosine-Hydroxylase Positive Dorsal Root Ganglia Neurons Frontiers in Cellular Neuroscience cancer chemotherapy neuropathy sensory vitamin E |
| title | Cisplatin Neurotoxicity Targets Specific Subpopulations and K+ Channels in Tyrosine-Hydroxylase Positive Dorsal Root Ganglia Neurons |
| title_full | Cisplatin Neurotoxicity Targets Specific Subpopulations and K+ Channels in Tyrosine-Hydroxylase Positive Dorsal Root Ganglia Neurons |
| title_fullStr | Cisplatin Neurotoxicity Targets Specific Subpopulations and K+ Channels in Tyrosine-Hydroxylase Positive Dorsal Root Ganglia Neurons |
| title_full_unstemmed | Cisplatin Neurotoxicity Targets Specific Subpopulations and K+ Channels in Tyrosine-Hydroxylase Positive Dorsal Root Ganglia Neurons |
| title_short | Cisplatin Neurotoxicity Targets Specific Subpopulations and K+ Channels in Tyrosine-Hydroxylase Positive Dorsal Root Ganglia Neurons |
| title_sort | cisplatin neurotoxicity targets specific subpopulations and k channels in tyrosine hydroxylase positive dorsal root ganglia neurons |
| topic | cancer chemotherapy neuropathy sensory vitamin E |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2022.853035/full |
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